This application aims to delineate the neural basis of late life anxiety and depressive disorders. As many as 15% of adults over the age of 60 years in the U.S. suffer from anxiety or depressive disorders. These disorders in late life are disabling, reduce the quality of life, impair cognitive processing and increase morbidity and mortality. Little is known about the neurocircuitry underlying these disorders in older adults, an issue that is further complicated by the neurodegenerative changes that accompany the aging process. Increased characterization of the neural basis of late life mood and anxiety disorders is essential for increasing our understanding of a) the etiology of these disorders;b) their differential diagnosis;c) their relationship to age- related neurodegeneration and cognitive decline;d) vulnerability and resilience factors;e) predictors of treatment response;and also for the f) establishment of the basis for development of rational therapeutics targeting defined neural circuits. We propose to provide this much-needed neurobiological foundation by investigating in patients with late life depression and anxiety innovative fMRI paradigms that we have utilized to identify differential neural substrates of depression and anxiety in young adults that both characterize and distinguish these disorders. To achieve our objective of characterizing late life MDD and GAD at a neural circuit level, we will apply these neuroimaging probes to 160 older adults (>60 years old) falling equally into four groups: GAD only, MDD only, comorbid GAD/MDD and healthy controls, while also examining non- emotional cognitive control processes that parallel emotion regulatory ones, and assessing a range of cognitive functions through neuropsychological testing. Our Specific Aims, based on our preliminary data and considerations regarding age-related cognitive decline, are: Aim 1: To examine if fMRI measures of emotional processing and regulation are associated with different patterns of impaired neurocircuitry in late life GAD versus late life MDD. Aim 2: To examine if neurocircuitry abnormalities in co-morbid late life GAD and MDD are additive. Aim 3: To examine if dysregulation of emotional processing in late life GAD and MDD is due to impaired executive control during cognitive processing. PUBLIC HEALTH RELEVANCE: The overall aim of this application is to investigate the neural basis of Late Life Depression and Anxiety utilizing a set of fMRI paradigms already demonstrated to provide a neuroimaging signature for depression and anxiety in young adults. The proposed study will not only extend previous findings into older adults, but also investigate the critical relationship between age- related cognitive dysfunction and deficits in emotion regulation. The Neurobiology of Psychiatric Disorders in late life is largely unknown, and is further complicated by the neurodegenerative changes that accompany the aging process. Little is known regarding the neurocircuitry of emotional regulation in late life GAD and MDD, and virtually nothing about Comorbid GAD and MDD. Understanding the neural basis of these disorders is of particular clinical importance since these disorders and their comorbidity are associated with greater resource utilization, morbidity, relapse rate and disability. The information yielded from the proposed work has the potential to inform the development of both pharmacological and non-pharmacological treatments for these disorders, as well as novel circuit-based interventions.